Natural Killer (NK) cells, key cells of the immune system are inactive in the absence of danger. Indeed, NK cells possess receptors on their surface capable of inhibiting their effector functions. NK cell activation is thus believed to be dependent in part on a loss of negative signaling. This occurs during viral infection or tumor development that induces down-regulation of several cell surface molecules. NK cells will detect these subtle modifications and eliminate these non-healthy cells. The laboratory recently made the surprising finding that, Killer Cell Lectin like Receptor G1 (KLRG1), an evolutionary conserved inhibitory receptor expressed at the NK cell surface is a ligand for Ncadherin and E-cadherin molecules. These classical cadherins, which are Ca2+ dependent, homophilic, cell adhesion molecules are expressed in almost all tissues and are transmembrane components of a number of cellular junctions. The fact that an immune receptor such as KLRG1 interacts with cadherin is intriguing and opens new unanticipated avenues of research. Our hypothesis is that the KLRG1/cadherin interaction may have an impact not only on immune cells such as NK cells but also on cells expressing E-cadherin such as epithelial cells. We therefore propose to study the consequence of cadherin engagement by KLRG1 at the cellular and molecular levels. In specific aim 1, we will first determine how KLRG1, after binding to its ligand E-cadherin, induces a signaling cascade. We will then investigate the role of cadherin/KLRG1 interaction during viral infection. To do this, a variety of in vivo approaches will be developed including the generation of retrogenic mice for expression of KLRG1 transgenes. In specific aim 2, we will examine whether cadherin engagement by KLRG1 induces cadherin phosphorylation, modifies cadherin/catenin complex stability and influence cellular functions. We believe this unexplored research will expand our current knowledge of NK cell biology and provide insights into the role of cadherins during the immune response to pathogens as well as the role of immune receptors in the maintenance of tissue structure integrity. PUBLIC HEALTH RELEVANCE: The main function of the immune response is to control and to eliminate pathogens. Understanding how the immune response develops and affects tissue integrity is critical for designing appropriate therapies to infectious diseases or cancer.